Fifty Shades of E<sup>rns</sup>: Innate Immune Evasion by the Viral Endonucleases of All Pestivirus Species
2022
Elena de Martin | Matthias Schweizer
The genus <i>Pestivirus</i>, family <i>Flaviviridae</i>, includes four historically accepted species, i.e., bovine viral diarrhea virus (BVDV)-1 and -2, classical swine fever virus (CSFV), and border disease virus (BDV). A large number of new pestivirus species were identified in recent years. A common feature of most members is the presence of two unique proteins, N<sup>pro</sup> and E<sup>rns</sup>, that pestiviruses evolved to regulate the host’s innate immune response. In addition to its function as a structural envelope glycoprotein, E<sup>rns</sup> is also released in the extracellular space, where it is endocytosed by neighboring cells. As an endoribonuclease, E<sup>rns</sup> is able to cleave viral ss- and dsRNAs, thus preventing the stimulation of the host’s interferon (IFN) response. Here, we characterize the basic features of soluble E<sup>rns</sup> of a large variety of classified and unassigned pestiviruses that have not yet been described. Its ability to form homodimers, its RNase activity, and the ability to inhibit dsRNA-induced IFN synthesis were investigated. Overall, we found large differences between the various E<sup>rns</sup> proteins that cannot be predicted solely based on their primary amino acid sequences, and that might be the consequence of different virus-host co-evolution histories. This provides valuable information to delineate the structure-function relationship of pestiviral endoribonucleases.
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